Intermediary compounds for the hemisynthesis of taxanes and preparation processes therefor

ABSTRACT

The present invention relates to new intermediates for the semisynthesis of taxanes and their preparation processes. It relates to derivatives of oxazolidines or oxazolidinones, as well as to new derivatives of baccatine III. The general process for the synthesis of taxanes according to the invention enables to obtain a product such as PACLITAXEL in only five steps from products available in the market, compared to nine steps in general, for processes of the prior art.

This application is a 371 of PCT/FR96/01679, dated Oct. 25, 1996.

The present invention relates to novel intermediates for thehemisynthesis of taxanes and to their processes of preparation.

Taxanes, natural substances with a diterpene skeleton which is generallyesterified by a β-amino acid side chain derived from N-alkyl- orN-aroylphenylisoserine, are known as anticancer agents. Several dozentaxanes have been isolated from Taxaceae of the genus Taxus, such as,for example, paclitaxel (R₁=Ac, R₂=Ph, R₃=R₄=H), cephalomanine, theirderivatives deacetylated in the 10 position, or baccatins (derivativeswithout side chain) represented by the formulae 1 and 2 below.

To avoid rapidly exhausting its original source, Taxus brevifolia,French researchers have sought to isolate paclitaxel from renewableparts (leaves) of T. baccata, the European yew. They have thusdemonstrated the probable biogenetic precursor of taxanes,10-deacetylbaccatin III, the springboard of choice for the hemisynthesisbecause of its relative abundance in leaf extracts.

The hemisynthesis of taxanes, such as paclitaxel or docetaxel (R₁=Ac,R₂=t-butyloxy, R₃=R₄=H), thus consists in esterifying the 13-hydroxyl ofa protected derivative of baccatin or of 10-deacetylbaccatin III with aβ-amino acid derivative.

Various processes for the hemisynthesis of paclitaxel or of docetaxelare described in the state of the art (EP-0 253 738, EP-0 336 840, EP-0336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO94/07879, WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO94/14787). Two recent works, I. Georg, T. T. Chen, I. Ojima, and D. M.Vyas, “Taxane Anticancer Agents, Basic Science and Current Status”, ACSSymposium Series 583, Washington (1995) and Matthew Suffness, “Taxol®Science and Applications” CRC Press (1995), 1500 references cited,comprise exhaustive compilations of hemisyntheses of taxanes.

The β-amino acid side chains derived from N-alkyl- orN-aroylphenylisoserine of paclitaxel or docetaxel are of (2R,3S)configuration and one of the main difficulties in the hemisynthesis oftaxanes is to obtain an enantiomerically pure product. The first problemconsists in obtaining a pure enantiomer of the phenylisoserinederivatives employed in the hemisynthesis of taxanes. The second problemconsists in retaining this enantiomeric purity during the esterificationof the baccatin derivative and the subsequent treatments of the productsobtained including deprotection of the hydroxyls and similar treatments.

Many studies on asymmetric synthesis involving derivatives of β-aminoacids have focused on the chemistry of isoserine and of its derivatives,β-amino acids for which a dehydrated cyclic form is a β-lactam (EP-0 525589). The majority of the various syntheses of phenylisoserinederivatives useful as precursors of taxane side chains focus on a commonintermediate, (2R,3R)-cis-β-phenylglycidic acid, which is subsequentlyconverted to β-phenylisoserine by reaction with ammonia (EP-0 495 718)or a nucleophile (Gou et al., J. Org. Chem., 1983, 58, 1287-89). Thesevarious processes require a large number of stages in order to produceβ-phenylisoserine of (2R,3S) configuration, necessarily with a stage ofracemic resolution by conventional selective crystallization techniques,either for cis-β-phenylglycidic acid or for β-phenylisoserine, orsubsequently, after conversion. Furthermore, in order to retain theenantiomeric purity of taxane side chain precursors during theesterification of the baccatin derivative, various means have beenprovided, in particular by using cyclic intermediates of blockedconfiguration, which remove the risks of isomerization duringesterification reactions under severe reaction conditions. Inparticular, they involve 13lactam (EP-0 400 971), oxazolidine (WO92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO94/12482), oxazinone (EP-0 428 376) or oxazoline (WO 94/14787)derivatives. These cyclic precursors are prepared from the correspondingβ-phenylisoserine derivative. As for the latter, the processes providedinvolve a large number of stages and a necessary racemic resolution inorder to obtain the desired taxane side chain precursor. It was thusimportant to develop a novel route for the improved synthesis ofintermediates which are taxane side chain precursors, in particular ofenantiomers of cis-β-phenylglycidic acid, of β-phenylisoserine and oftheir cyclic derivatives.

Finally, for the hemisynthesis of taxanes and in particular ofpaclitaxel, the sole appropriate baccatin derivative used until now isthat for which the 7-hydroxy radical is protected by a trialkylsilyl(EP-0 336 840, WO 94/14787), the deprotection of which is carried outexclusively in acidic medium. It was thus also important to employ novelprotective groups for the hydroxyl functional group which in particularmake possible selective protection of the 7-hydroxy radical and inaddition allow a wider choice of operating conditions for thedeprotection stage.

The present invention relates first of all to an improved process forthe preparation of taxane side chain precursors.

The process according to the invention comprises converting acis-β-arylglycidate derivative of general formula I

in which

Ar represents an aryl, in particular phenyl, and

R represents a hydrocarbon radical, preferably a linear or branchedalkyl or a cycloalkyl optionally substituted by one or more alkylgroups,

wherein said process is carried out so as to regio- andstereospecifically introduce the β-N-alkylamide and the a-hydroxyl ortheir cyclic precursors in a single stage by a Ritter reaction.Depending on the reaction mixture, two types of Ritter reaction are thusdistinguished: one with opening of the oxetane, resulting in a linearform of the chain which is directly and completely functionalized, theother resulting in the direct formation of an oxazoline. The “*” symbolindicates the presence of an asymmetric carbon, with an R or Sconfiguration. In both cases, the Ritter reaction is stereospecific,with retention of C-2 configuration and inversion of C-3 configuration.The process according to the invention is advantageously carried out onone of the enantiomers of the cis-β-arylglycidate derivative of generalformula 1, so as to obtain the corresponding enantiomer of the linearchain or of the oxazoline, without subsequently requiring a racemicresolution. According to the method of preparation of thecis-β-arylglycidate derivative of general formula I described below, Rrepresents an optically pure enantiomer of a highly sterically hinderedchiral hydrocarbon radical, advantageously a cycloalkyl substituted byone or more alkyl groups, in particular a cyclohexyl. R will thenpreferably be one of the enantiomers of the menthyl radical, inparticular (+) menthyl.

1. Direct synthesis of the linear chain

The direct synthesis of the linear chain by the Ritter reactioncomprises reacting a cis-β-arylglycidate derivative of general formula Idefined above with a nitrile of formula

R₂—CN

in which

R₂ represents an aryl radical, preferably a phenyl,

in the presence of a proton acid, such as sulphuric acid, perchloricacid, tetrafluoroboric acid, and the like, and of water.

A β-arylisoserine derivative of general formula IIa

in which Ar, R and R₂ are defined above,

is then obtained.

The reaction is carried out with inversion of the configuration of theC-3 of the cis-β-phenylglycidate derivative. Thus, starting from a(2R,3R)-cis-β-phenylglycidate derivative, the correspondingβ-arylisoserine derivative of (2R,3S) configuration is obtained.

The Ritter reaction is carried out in an appropriate solvent, at atemperature ranging from −75 to +25° C.

The appropriate solvent can be the nitrile itself, when it is liquid atthe reaction temperature, or alternatively the acid itself (sulphuric,perchloric or tetrafluoroboric), or a solvent, such as, for example,methylene chloride or ethyl ether. The proton acids conventionally usedcan contain the water necessary for the hydrolysis.

When benzonitrile (R₂=phenyl) is employed with the cis-β-arylglycidateof general formula I of (2R,3R) configuration for which Ar represents aphenyl, then the corresponding β-arylisoserine derivative of generalformula IIa of (2R,3S) configuration for which Ar and R₂ represent aphenyl is directly obtained, which product is none other than theprecursor of the side chain of paclitaxel.

2. Direct synthesis of the cyclic chain

In this method, a Ritter reaction is also carried out with a nitrile offormula

R′₂—CN

in which R′₂ represents R₂ defined above or a lower alkyl or lowerperhaloalkyl radical, such as trichloromethyl, in the presence of aLewis acid, in particular the boron trifluoride acetic acid complex,boron trifluoride etherate, antimony pentachloride, tin tetrachloride,titanium tetrachloride, and the like, or of a proton acid, such as, forexample, tetrafluoroboric acid, the reaction being carried out inanhydrous medium.

As for the synthesis of the linear chain, the solvent can be the nitrileitself, when it is liquid at the reaction temperature, or alternativelyan appropriate solvent, such as, for example, methylene chloride orethyl ether. The reaction temperature also ranges from −75 to +25° C.

In the absence of water, an intramolecular Ritter reaction is carriedout and the oxazoline of general formula IIb

in which Ar, R and R′₂ are as defined above,

is obtained.

As in the Ritter reaction in the presence of water, the reaction iscarried out with inversion of the configuration of the C-3 of thecis-β-phenylglycidate derivative. Thus, starting from a(2R,3R)-cis-β-phenylglycidate derivative, the corresponding oxazoline of(2R, 3S) configuration is obtained.

For both Ritter reactions, in order to avoid the formation of a freecarbocation which is the cause of many potential side reactions, thereactants are preferably added in the following order: i) the complexbetween the nitrile and the acid is first formed, then ii) the acidcatalyst is added to the mixture composed of the oxirane and thenitrile.

The products obtained by this first stage, which are β-arylisoserinederivatives of general formula Ia or oxazoline derivatives of generalformula IIb, can be further converted in a second optional stagedescribed hereinbelow or then converted to acids by controlledsaponification, before being coupled to a protected baccatin derivativefor the hemisynthesis of taxanes, in particular of paclitaxel and its10-deacetylated derivatives or of docetaxel. In the case ofβ-arylisoserine derivatives of general formula IIa, the saponificationcan be preceded by a conventional stage of protection of the hydroxyl byan appropriate protective group. A derivative of general formula II′a

in which

Ar, R and R₂ are defined above, and

GP represents a protective group for the hydroxyl functional group whichis appropriate for the synthesis of taxanes, in particular chosen fromalkoxy ether, aralkoxy ether, aryloxy ether or haloalkoxycarbonylradicals, such as, for example, methoxymethyl, 1-ethoxyethyl,benzyloxymethyl or (β-trimethylsilylethoxy)methyl groups,tetrahydropyranyl or β-alkoxycarbonyl (TrOC) radicals, β-halogenated oralkylsilyl ethers or alkoxyacetyl, aryloxyacetyl, haloacetyl or formylradicals, is then obtained.

3. Conversion of the derivatives of formula ha or IIb

The derivatives of general formula IIa or IIb obtained above canoptionally be converted into novel intermediates which are side chainprecursors in the hemisynthesis of taxanes. These conversions take placewith retention of the configuration of the C-2 and C-3 positions. Thenovel intermediates obtained will thus have the same stereochemistry asthe derivatives of formula Ia or IIb from which they derive. Theproducts obtained in this second stage are subsequently converted intoacids by controlled saponification, before being coupled with aprotected baccatin derivative for the hemisynthesis of taxane, inparticular of paclitaxel or of docetaxel.

3.1 Cyclization of the derivatives of general formula IIa

The derivatives of general formula IIa can subsequently be convertedinto oxazolines of formula IIb according to conventional methods of thestate of the art (WO 94/14787).

The β-arylisoserine derivatives of general formula Ia can also beconverted into novel oxazolidinone cyclic intermediates of generalformula III′a

in which Ar and R are defined above and R″₂ represents R′₂ definedabove, an alkoxy radical, preferably a t-butoxy radical, or a linear orbranched alkyl radical comprising at least one unsaturation, for examplea 1-methyl-1-propylene radical, and the corresponding dialkyl acetals.

The oxazolidinones of general formula III′a are obtained first of all byreacting a β-arylisoserine derivative of general formula IIa with ahaloalkoxycarbonyl ester, in particular 2,2,2-trichloroethoxycarbonyl(TrOC), and then by cyclization in the presence of a strong organicbase, such as diazabicycloundecene (DBU). An oxazolidinone derivative ofgeneral formula IIIa

which Ar and R are defined above,

is then obtained.

The derivatives of general formula IIIa can also be obtained by directsynthesis, by reacting the β-arylglycidate derivatives of formula II′awith urea.

The acylated derivatives of general formula II′a are obtained byintroducing the R″₂—CO— radical according to the usual acylationtechniques, in the presence of an appropriate acylating agent, forexample an acyl halide of formula R″₂—CO—X, in which R″₂ is definedabove and X represents a halogen, or an anhydride of the correspondingacid.

The dialkyl acetals are obtained according to the usual techniques forthe formation of acetals.

3.2 Opening of the oxazoline of general formula IIb

The β-arylisoserine derivative of general formula IIIb

in which Ar, R and R′₂ are defined above,

is obtained by hydrolysis of the oxazoline of general formula IIb inacidic medium.

Advantageously, when R′₂ represents a lower perhaloalkyl, such astrichloromethyl, the R′₂—CO— radical constitutes a protective group forthe hydroxyl functional group.

This taxane side chain precursor can then be converted into amides ofgeneral formula III′b

in which

Ar, R, R′₂ and R″₂ are defined above.

The precursor of the side chain of paclitaxel (R″₂=phenyl) or ofdocetaxel (R″₂=t-butoxy) can thus be obtained without distinction.

4. Preparation of the cis-β-arylglycidic acid derivative of formula I

The cis-β-arylglycidic acid derivative of formula I can be preparedaccording to conventional processes of the state of the art or by simpleesterification of cis-β-arylglycidic acid with the corresponding alcoholR—OH. In order to improve the overall yield in the synthesis of taxanechain precursors, a cis-β-arylglycidate derivative of general formula I

in which

Ar is defined above and

R represents an optically pure enantiomer of a highly stericallyhindered chiral hydrocarbon radical,

is prepared in the process according to the invention by reacting thealdehyde of formula

Ar—CHO

with the haloacetate of formula

X—CH₂—COOR

Ar and R being defined above and

X representing a halogen, in particular a chlorine or a bromine.

Advantageously, the optically pure enantiomer of a highly stericallyhindered chiral hydrocarbon radical is a cycloalkyl substituted by oneor more alkyl groups, in particular a cyclohexyl.

The method involves a Darzens' reaction through which a mixture of thetwo diastereoisomers, ester of (2R,3R)-cis-β-arylglycidic acid and(2S,3S)-cis-β-arylglycidic acid and of an optically pure enantiomer ofthe chiral alcohol R—OH, is obtained, since the Darzens' reaction,carried out with a highly sterically hindered haloacetate, resultsessentially in the cis form of the β-arylglycidate. Advantageously, thehighly sterically hindered chiral hydrocarbon radical will be chosen sothat it allows the physical separation of the two diastereoisomers fromthe reaction mixture, for example by selective crystallization, withoutrequiring a stereospecific separation of the desired enantiomer at theend of the reaction by conventional crystallization or chiral columnchromatography methods.

Advantageously, R—OH represents menthol, one of the rare highlysterically hindered chiral alcohols which is economic and commerciallyavailable in both its enantiomeric forms.

In the process for the synthesis of a precursor of the taxane sidechain, the goal is to prepare a cis-β-phenylglycidate of (2R,3R)configuration. In this case, the highly sterically hindered chiralhydrocarbon radical R will be selected so that the diastereoisomer ofthe cis-β-phenylglycidate of (2R,3R) configuration crystallizes firstfrom the reaction mixture. When R—OH is menthol, (+)-menthol isadvantageously employed.

The asymmetric Darzens' reaction is carried out in the presence of abase, particularly an alkali metal alkoxide, such as potassiumtert-butoxide, or an amide, such as lithium bistrimethylsilylamide, inan appropriate solvent, in particular an ether, such as ethyl ether, ata temperature ranging from −78° C. to 25° C. The reaction results in adiastereoisomeric mixture composed virtually exclusively of thecis-glycidates, which can reach a yield of greater than 95%, in theregion of 97%. Treatment of the isolated product in an appropriatesolvent, in particular a methanol/water mixture, makes it possible toreadily obtain physical separation of the required diastereoisomers. Byfractional crystallization (2 stages), rapid enrichment in the desireddiastereoisomer is obtained, with a diastereoisomeric purity of greaterthan 99%.

The latter point is particularly important because it conditions theisomeric purity of the final taxane, the undesirable diastereoisomersexhibiting their own biological activity which is different from that ofthe desired taxane.

It is remarkable to observe that the selective use of the twoenantiomers of the menthyl ester makes it possible to access, using thesame process, the 2 precursor diastereoisomers of the two enantiomers ofglycidic acid.

In addition to a fairly high yield of pure isolated diastereoisomer (upto 45%), the diastereoisomeric purity of the major product of thereaction, the ease of implementation of the reaction, the simplicity andthe speed of the purification, and the low cost of the reactants andcatalysts make the industrial synthesis of this key intermediate in theasymmetric synthesis of β-amino acids easy and economical to access.

When a derivative of general formula I obtained by an asymmetricDarzens' reaction is used in the process according to the invention, thederivatives of general formulae IIa, II′a, IIb, IIIa, IIIb and III′bdefined above are then obtained for which R represents an optically pureenantiomer of a highly sterically hindered chiral hydrocarbon radical,such as a cycloalkyl substituted by one or more alkyl groups, inparticular a cyclohexyl, preferably menthyl, advantageously (+)-menthyl.

The present invention also relates to these derivatives, which are ofuse as intermediates in the synthesis of taxane side chains.

It should be noted that the present process constitutes a very rapidaccess to the substituted chiral oxazolines already described in theliterature (WO 94/14787), in 3 stages from commercially availableproducts, instead of 6 to 8 stages.

5. Controlled saponification

A controlled saponification of the derivatives of general formulae IIa,II′a, IIb, IIa, IIIb and III′b is carried out under mild conditions, soas to release the acidic functional group while retaining the structureof the said derivatives, for example in the presence of an alkali metalcarbonate in a methanol/water mixture.

After controlled saponification, the derivatives of general formulaeIIa, II′a, IIb, IIIa, IIIb and III′b defined above in which R representsa hydrogen atom are obtained, which derivatives can be employed directlyin the hemisynthesis of taxanes by coupling with an appropriate baccatinIII derivative.

6. Hemisynthesis of taxanes

6.1 Esterification

The present invention thus also relates to a process for thehemisynthesis of taxanes of general formula IV,

C—B  (IV)

in which

C represents a side chain chosen from the radicals of followingformulae:

in which Ar, R₂, R′₂, R″₂, R₃ and GP are defined above, and

B represents a radical derived from baccatin III of general formula V

in which

Ac represents the acetyl radical,

Bz represents the benzoyl radical,

Me represents the methyl radical,

R₄ represents an acetyl radical or a protective group for the hydroxylfunctional group GP1, and

R₅ represents a protective group for the hydroxyl functional group GP2,

by esterification of an appropriate baccatin III derivative of generalformula V, carrying a C-13 hydroxyl functional group, with one of thederivatives of general formulae IIa, II′a, IIb, IIIa, III′a, IIIb andIII′b defined above, in which R represents a hydrogen atom, underconventional conditions for the preparation of taxanes as defined in thestate of the art (in particular: EP-0 253 738, EP-0 336 840, EP-0 336841, EP-0 495 718, WO 92109589, WO 94/07877, WO 94/07878, WO 94107879,WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO 94/14787).

The GP1 and GP2 protective groups are, independently of one another,conventional groups employed in the hemisynthesis of taxanes, such astrialkylsilyls (EP-0 336 840) or TrOC (EP-0 336 841).

GP1 and GP2 also represent, independently of one another, linear orbranched hindered haloalkoxycarbonyl radicals comprising at least onehalogen atom. They are advantageously radicals in which the alkylresidue comprises between 1 and 4 carbon atoms and 3 or 4 halogen atoms,preferably chosen from 2,2,2-tribromoethoxycarbonyl,2,2,2,1-tetrachloroethoxycarbonyl, 2,2,2-trichloro-t-butoxycarbonic andtrichloromethoxycarbonyl radicals, radicals which are all more hinderedthan the haloalkoxycarbonyl (TrOC) used until now to protect taxanes inthe 7 position.

GP1 and GP2 also represent, independently of one another, acyl radicalsin which the carbon α to the carbonyl functional group carries at leastone oxygen atom.

These acyl radicals are described in particular in EP-0 445 021. Theyare advantageously alkoxy- or aryloxyacetyl radicals of formula

R₆—O—CH₂—CO—

in which R₆ represents a sterically hindered alkyl radical, a cycloalkylradical or an aryl radical, or arylidenedioxyacetyl radicals of formula

in which Ar″ represents an arylidene radical.

Sterically hindered alkyl is preferably understood to mean a linear orbranched C₁-C₆ alkyl radical substituted by one or more bulkysubstituents chosen from halogens or linear or branched C₁-C₆ alkyl,linear or branched C₁-C₆ alkoxy or C₃-C₆ cycloalkyl or aryl radicals. Itwill be, for example, a tert-butyl or triphenylmethyl radical.

Cycloalkyl is preferably understood to mean a C₃-C₆ cycloalkyl radicaloptionally substituted by one or more bulky substituents chosen fromhalogens or linear or branched C₁-C₆ alkyl, linear or branched C₁-C₆alkoxy or aryl radicals. Advantageously, it is a cyclohexyl radicalsubstituted by one or more linear or branched C₁-C₆ alkyl radicals, suchas, for example, menthyl, its racemate or its enantiomers and theirmixtures in all proportions.

Aryl is preferably understood to mean a phenyl, naphthyl, anthryl orphenantryl radical optionally substituted by one or more bulkysubstituents chosen from halogens or linear or branched C₁-C₆ alkyl,linear or branched C₁-C₆ alkoxy or aryl radicals, in particular thephenyl radical. It is preferably a phenyl radical optionally substitutedby one or two above bulky substituents ortho- and ortho′- to the etherbond.

Finally, arylidene is preferably understood to mean a phenylene,naphthylene, anthrylene or phenanthrylene radical optionally substitutedby one or more bulky substituents chosen from halogens or linear orbranched C₁-C₆ alkyl, linear or branched C₁-C₆ alkoxy or aryl radicals,in particular the phenyl radical.

GP1 and GP2 also represent, independently of one another, atrialkylgermanyl radical or together form a divalent radical of formula

—SiR₇—O—SiR₈—

in which

R₇ and R₈, independently of one another, represent a sterically hinderedalkyl radical as defined above; in particular, R₇ and R₈ each representan isopropyl radical.

6.2 Optional opening

When C represents a radical of formula IIb or IIIa, the oxazoline ringis opened in order to obtain a taxane derivative of formula VI

in which

Ac, Bz, Me, Ar, R′₂, R₄ and R₅ are defined above.

The IIb, IIIa and III′a radicals are generally opened by hydrolysis inacidic or basic medium. The radical of formula IIb can be openedaccording to the methods described in the state of the art (inparticular WO 94/14787), by hydrolysis in acidic medium, followed bytreatment in basic medium, in order to obtain the derivative of generalformula VI.

6.3 Deprotection

Finally, the hydroxyls of the derivatives of general formula V or VI aredeprotected by replacing the protective groups for the hydroxylfunctional group, GP (when C represents the II′a radical), GP1 (when R₄is other than an acetyl) and GP2, by a hydrogen atom according to theusual techniques.

For the derivatives of general formula V in which C represents a radicalof formula IIb or IIIa and GP1 and/or GP2 are, independently of oneanother, conventional groups employed in the hemisynthesis of taxanes,such as trialkylsilyls, the deprotection is carried out simultaneouslywith the opening described above.

When GP1 and/or GP2 are bulky haloalkoxycarbonyl radicals, deprotectionis carried out according to the usual techniques described for TrOC, bythe action of zinc or of zinc doped with heavy metals, such as copper,in an organic solvent, in particular in acetic acid, tetrahydrofuran orethyl alcohol, with or without water.

When GP1 and/or GP2 are acyl radicals in which the carbon a to thecarbonyl functional group carries at least one oxygen atom, deprotectionis carried out in basic medium by saponification in methanol at lowtemperature, advantageously with ammonia in methanol at a temperature ofless than 10° C., preferably in the region of 0° C.

For the case where C represents a radical of formula IIb, opening of theoxazoline is carried out simultaneously with deprotection in basicmedium, in order to result, in one stage, in the corresponding taxanederivative of general formula VI in which R₄ represents an acetylradical or a hydrogen atom and R₅ represents a hydrogen atom, incontrast to the opening in acidic medium described in the state of theart, which requires a second stage in basic medium.

The known protective groups are removed using known methods and theoxazoline chain, when it was present, opened out by hydrolysis, givingtaxanes in every respect identical to the reference taxanes. By way ofexample, without, however, limiting the scope of the invention,paclitaxel, 10-deacetyltaxol, cephalomanine and docetaxel can beobtained from the corresponding protected derivatives.

The deblocking of the acyls in which the carbon a to the carbonylfunctional group carries at least one oxygen atom was first attemptedunder the conventional conditions regarded as the mildest, that is tosay zinc acetate in methanolic medium at reflux. In this case, as thereaction was complete in a few hours (compared to a few days foracetates), the C-7 epimer resulting from the conventionalretroaldolization equilibrium was always isolated, in addition to thedesired product. It being presumed that, even under the neutral, indeedslightly acidic, conditions, the main agents responsible were methanoland especially the temperature, we returned to the standard conditionsfor deblocking acyls described by early writers, by saponification inbasic medium in ethanol at low temperature. Under these conditions, nosignificant epimerization was observed. By way of example, we obtainedpaclitaxel, 10-deacetyltaxol, cephalomanine and docetaxel, in everyrespect identical to the reference taxanes, from the correspondingalkoxy- or aryloxyacetylated derivatives.

Finally, it should be noted that all the methods described above, whichare nevertheless targeted at improving the overall yield of thehemisynthesis, consist in synthesizing the phenylisoserine chainbeforehand, for the purpose of converting it into one of the cyclicstructures mentioned above (β-lactams, oxazolidines or oxazolines).Thus, paradoxically, the apparent better performances in the coupling ofthese cyclic structures only compensates for the fall in overall yieldcaused by the addition of ring creation stages to the synthetic sequencefor the linear chain (i.e., a total of 9 stages). For the generalprocess for the synthesis of taxanes according to the invention, aproduct such as paclitaxel is obtained in only 5 stages:

(1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidate

(1S,2R,5S)-(+)-menthyl(4S,5R)-2,4-diphenyl-4,5-dihydroxazole-5-carboxylate

saponification

hemisynthesis (esterification)

opening and deprotection.

Finally, the present invention relates to the synthetic intermediates ofgeneral formulae IV, V and VI described above which are of use in thegeneral synthesis of taxanes, a subject of the present invention.

Generally, hydroxycarbon radical is preferably understood to mean,according to the invention, a saturated or unsaturated hydrocarbonradical which can comprise one or more unsaturations, such as anoptionally unsaturated linear or branched alkyl, an optionallyunsaturated cycloalkyl, an aralkyl or an aryl, it being possible foreach optionally to be substituted by one or more substituents, inparticular alkyl substituents.

Linear or branched alkyl is preferably understood to mean, according tothe invention, a C₁-C₆ alkyl, in particular chosen from the methylradical, ethyl radical, propyl radical, isopropyl radical, butyl radicaland its various branched isomers, such as, for example, tert-butyl,pentyl radical and hexyl radical and their various branched isomers.This definition also applies to the alkyl residues of the alkoxy oraralkoxy radicals.

Cycloalkyl is preferably understood to mean, according to the invention,a C₃-C₆ cycloalkyl, in particular chosen from the cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl radicals.

Aryl is preferably understood to mean, according to the invention, anaromatic or heteroaromatic radical, in particular chosen from thephenyl, naphthyl, anthryl, phenantryl, pyridyl or pyrimidyl radicals andthe like.

Finally, halogen is preferably understood to mean chlorine, bromine oriodine. The haloalkoxycarbonyl radicals are preferably radicals in whichthe alkyl residue comprises between 1 and 4 carbon atoms and 3 or 4halogen atoms.

The general process for the synthesis of taxanes according to theinvention is repeated in Scheme 1 below, wherein R represents(+)-menthyl and R₂ or R′₂ represent phenyl.

The final stage in the hemisynthesis of taxanes by the process accordingto the invention is summarized in Schemes 2 and 3 below. Scheme 2summarizes the synthesis of paclitaxel from derivatives of formula IVdefined above in which C represents a radical of formulae IIb or III′a.Scheme 3 summarizes the synthesis of 10-deacetyltaxol from a derivativeof formula IV in which C represents a radical of formula IIb.

Of course, the same synthetic schemes can be used for the otherdefinitions of the substituents.

EXAMPLES

I. Taxane side chain precursors

Example 1

(1S,2R,5S)-(+)-Menthyl chloroacetate

57 mL (0.704 mol) of anhydrous pyridine were added to a stirred solutionat room temperature of 100 g (0.640 mol) of (1S,2R,5S)-(+)-menthol in 1L of dry dichloromethane. After stirring for a few minutes, 56 mL (0.704mol) of chloroacetyl chloride were subsequently added and the reactionwas allowed to continue for 30 min. After monitoring by T.L.C., 50 g ofcrushed ice were added and the reaction mixture was left vigorouslystirring for 1 h. After diluting with 100 mL of dichloromethane, theorganic phase was washed several times with a saturated aqueous sodiumchloride solution (200 mL), dried over MgSO₄ and then concentrated underreduced pressure. After purifying the crude product thus obtained bysilica gel chromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate,20/1), 146 g of (1S,2R,5S)-(+)-menthyl chloroacetate were obtained inthe form of a syrup.

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 4.77 (1H, dt), 4.06 and 4.02 (2H, 2d,J=13.6 Hz), 2.02 (1H, m, J=11.8 Hz), 1.87 (1H, m, J=7 and 2.6 Hz), 1.69(2H, m), 1.50 (1H, m), 1.43 (1H, m, J=11.7 and 3 Hz), 1.07 (1H, m), 1.02(1H, q, J=11.8 Hz), 0.92 and 0.90 (6H, 2d, J=6.4 Hz), 0.89 (1H, m), 0.77(3H, d, J=7 Hz).

Example 2

(1S,2R,5S)-(+)-Menthyl (2R,3R)-3-phenylglycidate

69 mL (0.686 mol) of benzaldehyde were added to a stirred solution atroom temperature of 152 g (0.653 mol) of (1S,2R,5S)-(+)-menthylchloroacetate in 600 mL of anhydrous ethyl ether. After stirring for afew minutes, the solution was cooled to −78° C. under an inertatmosphere, a suspension of 85 g (0.718 mol) of potassium tert-butoxidein 400 mL of anhydrous ethyl ether was subsequently added over 2 h andthe reaction mixture was allowed to return to room temperature. Aftermonitoring by T.L.C., the organic part was diluted with 200 mL ofdichloromethane, washed several times with a saturated sodium chloridesolution, dried over MgSO₄ and concentrated under reduced pressure. 200g of a crude product were thus obtained in the form of a syrupcontaining four diastereoisomers (of which two were cis and two weretrans), which was subjected as-is to a fractional crystallization.

In a first step, the solution of the crude product in 2 L of methanolwas brought to 60° C., to which 700 mL of osmosed water were graduallyadded, and was left for 16 h at room temperature without being subjectedto vibrations. A yellow-colored lower solid phase rich in trans isomerswas discarded and the white crystals of the upper phase, which are richin cis isomers, were separated by filtration. The crystals thus obtainedwere redissolved in 2 L of methanol brought to 60° C., 500 mL of osmosedwater were added, until a persistent cloudiness was obtained, and themixture was left for 16 h at room temperature. Three additionalcrystallizations, carried out according to the same process but withreduced volumes of methanol (1 L) and water (200 mL), were necessary toobtain 23 g of (1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidate in thecrystalline state with an HPLC purity>99% (Yd=12%).

The compound obtained exhibited the following characteristics:

M.p.=104° C.

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.40 (2H, dd, J=7.8 Hz and 1.7 Hz), 7.32(3H, m), 4.58 (1H, dt, J=10.9 Hz and 4.2 Hz), 4.26 (1H, d, J=4.6 Hz),3.83 (1H, d, J=4.8 Hz), 1.6 to 0.85 (9H, m), 0.78 (3H, d, J=7 Hz), 0.75(3H, d, J=6.4 Hz), 0.62 (3H, d, J 6.9 Hz).

X-ray diffraction of a (1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidatesingle crystal for the purpose of the indirect determination of theabsolute configuration:

The single crystal was obtained from a crystalline suspension resultingfrom the addition, while hot, of the non-solvent (water) to asemi-saturated solution of the glycidate in methanol. On slow cooling,fine needles with a purity of 99.95% (HPLC) were deposited by thissolution, which needles were stored under moist conditions until thefinal selection.

The selected sample (fine needle with dimensions 0.12×0.12×0.40 mm) wasstudied on a CAD4 Enraf-Nonius automatic diffractometer (molybdenumradiation with graphite monochromator). The unit-cell parameters wereobtained by refinement of a set of 25 reflections with a high thetaangle. Data collection (2θmax=50°, scanning ω/2θ=1, t_(max)=60 s, HKLdomain: H 0.6 K 0.14 L 0.28, intensity controls without significantdrift (0.1%)) provided 1888 reflections, 1037 of which with I>1.5 σ(I).C₁₉H₂₆O₃: Mr=302.42, orthorhombic, P2₁2₁2₁, a=5.709(11), b=12.908(4),c=24.433(8) Å, V=1801(5) Å⁻³, Z=4, D_(z)=1.116 Mg.m⁻³, λ(MoKα)=0.70926Å, μ=0.69 cm⁻¹, F(000)=656, T=294 K, final R=0.072 for 1037observations.

After Lorenz corrections and polarization corrections, the structure wassolved using Direct Methods which made it possible to locate themajority of the nonhydrogen atoms of the molecule, the remaining atomsbeing located by Fourier differences and successive scaling operations.After isotropic refinement (R=0.125) and then anisotropic refinement(R=0.095), most of the hydrogen atoms were located using a Fourierdifference (between 0.39 and 0.14 eÅ⁻³), the others being positioned bycalculation. The complete structure was refined by whole matrix (x, y,z, β_(ij), for C and O, x, y, z for H; 200 variables and 1037observations; w=1/σ(F_(o))²=[σ²(I)+(0.04F_(o) ²)²]^(−½)) resulting inR=0.080, R_(w)=0.072 and S_(w)=1.521 (residue Δp≦0.21 eÅ⁻³).

The scattering factors are taken from the International Tables ofcrystallography [International Tables for X-ray Crystallography (1974),Vol. IV, Birmingham: Kynoch Press (Current distributor D. Reidel,Dordrecht)]. The calculations were carried out on a Hewlett-Packard9000-710 for the determination of the structure [Sheldrick, G. M.(1985), Crystallographic Computing 3: Data Collection, StructureDetermination, Proteins and Databases, edited by G. M. Sheldrick, C.Kruger and R. Goddard, Oxford, Clarendron Press] and on a DigitalMicroVax 3100 for the other calculations with the MOLEN suite ofprograms [Fair, C. K. (1990), MOLEN: An Interactive Intelligent Systemfor Crystal Structure Analysis, Enraf-Nonius, Delft, The Netherlands].

A (1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidate sample, by treatmentwith sodium methoxide in methanol, made it possible to obtain thecorresponding methyl phenylglycidate, the characteristics of which wereas follows:

[α]_(D) ²⁸=+12 (c=1.15, chloroform)

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.40 (2H, d, J=8 Hz), 7.32 (3H, m), 4.26(1H, d, J=4.6 Hz), 3.84 (1H, d, J=4.6 Hz), 3.55 (3H, s).

Example 3

(1S,2R,5S)-(+)-Menthyl(4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylate

15 mL (0.109 mol) of a 54% solution of tetrafluoroboric acid in etherwere added over 10 min to a stirred solution, under an inert atmosphereat −65° C., of 30 g (0.0993 mol) of (1S,2R,5S)-(+)-menthyl(2R,3R)-3-phenylglycidate and 305 mL (2.98 mol) of benzonitrile in 1.5 Lof anhydrous dichloromethane. The reaction was allowed to continue at−65° C. for 1 h and, after monitoring by T.L.C., 300 mL of a saturatedaqueous sodium hydrogencarbonate solution were added and the reactionmixture was allowed to return to room temperature with stirring. Afterextracting the aqueous phase with dichloromethane (2×200 mL), thecombined organic phases were washed with a saturated sodium chloridesolution (200 mL) and with water (50 mL) and dried over MgSO₄. Afterconcentrating under reduced pressure and removing the residualbenzonitrile under high vacuum at 50° C., the crude product obtained waspurified by silica gel chromatography (15-40 μm) (eluent:cyclohexane/ethyl acetate, 20/1).

32 g of (1S,2R,5R)-(+)-menthyl(4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylate were thus isolatedin the form of a colorless syrup (Yd=80%) which exhibited the followingcharacteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.1 Hz), 7.54 (1H, t,J=7.4 Hz), 7.46 (2H, t, J=7.4 Hz), 7.34 (5H, m), 5.40 (1H, d, J=6.4 Hz),4.88 (1H, d, J=6.4 Hz), 4.85 (1H, dt, J=10.9 and 4.4 Hz), 2.09 (1H, m),1.84 (1H, m, J=7 and 2.7 Hz), 1.71 (1H, m), 1.69 (1H, m), 0.94 (3H, d,J=6.5 Hz), 0.9 (1H, m), 0.85 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz).

Example 4

(4S,5R)-2,4-Diphenyl-4,5-dihydrooxazole-5-carboxylic acid

25 mL of a solution of 6 g (43.2 mmol) of potassium carbonate in osmosedwater were added to a stirred solution at room temperature of 3.5 g(8.64 mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylate in methanol (70mL) and the reaction was left to continue for 16 h at room temperature.After monitoring by T.L.C., the reaction mixture was concentrated underreduced pressure. The aqueous phase thus obtained was washed withdichloromethane (3×100 mL), acidified to pH 2 by slow addition of 20 mLof a 1M aqueous HCl solution and extracted with ethyl acetate (3×100mL). The combined organic extraction phases were dried (MgSO₄) andconcentrated under reduced pressure.

2.26 g of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid werethus obtained in the form of a white powder (Yd=98%) which exhibited thefollowing characteristics:

[α]_(D) ²=+27.7 (c=0.99, CH₂Cl₂/MeOH, 1/1)

F=201-202° C.

400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 7.99 (2H, d, J=7.3 Hz), 7.64 (1H, t,J=7.4 Hz), 7.55 (2H, t, J=7.7 Hz), 7.36 (5H, m), 5.40 (1H, d, J=6.3 Hz),4.99 (1H, d, J=6.4 Hz).

Example 5

(1S,2R,5S)-(+)-Menthyl (2R,3S)-N-benzoyl-3-phenylisoserinate

15 mL of a 1 M aqueous HCl solution were added to a stirred solution atroom temperature of 1 g (2.47 mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylate in a mixture ofmethanol (15 mL) and tetrahydrofuran (15 mL). The reaction mixture wasbrought for 1 h to reflux and, after monitoring by T.L.C. and returningto room temperature, a saturated aqueous sodium hydrogencarbonatesolution (45 mL) was gradually added until a basic pH was obtained.After stirring for 48 h at room temperature, the aqueous phase obtainedafter concentrating under reduced pressure was extracted withdichloromethane (100 mL). The aqueous phase was washed with a saturatedsodium chloride solution (2×50 mL), dried over MgSO₄ and concentratedunder reduced pressure and the residue obtained was chromatographed onsilica gel (15-40 μm) (eluent: dichloromethane/methanol, 95/05).

0.835 g of (1S,2R,5S)-(+)-menthyl (2R,3S)-N-benzoyl-3-phenylisoserinatewas thus isolated in the form of a white solid (Yd=80%) which exhibitedthe following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.77 (2H, d, J=7.2 Hz), 7.51 (1H, t,J=7.3 Hz), 7.45 (4H, m), 7.36 (2H, t, J=7.2 Hz), 7.29 (1H, t, J=7.2 Hz),7.04 (1H, d, J=9.2 Hz), 5.78 (1H, dd, J=9.2 and 2.1 Hz), 4.79 (1H, dt,J=10.9 and 4.4 Hz), 4.63 (1H, broad s), 3.35 (1H, broad s), 1.81 (2H,m), 1.67 (3H, m), 1.5 to 1.36 (2H, m), 1.09 to 0.91 (2H, m), 0.89 (3H,d, J=6.9 Hz), 0.77 (3H, d, J=6.5 Hz), 0.74 (3H, d, J=6.9 Hz).

Example 6

(1S,2R,5S)-(+)-Menthyl(2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinate

0.255 g (2.08 mmol) of 4-dimethylaminopyridine was added to a solutionof 0.8 g (1.89 mmol) of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-3-phenylisoserinate in 10 mL of anhydrousdichloromethane. After stirring for a few minutes at room temperature,477 μL (2.84 mmol) of triethylsilyl chloride were added over 5 min.After stirring for 1 h at room temperature and monitoring by T.L.C., thereaction mixture was diluted with

100 mL of dichloromethane. The organic phase was washed with a saturatedaqueous sodium hydrogencarbonate solution (2×20 mL) and with a saturatedsodium chloride solution (50 mL), dried over MgSO₄ and concentratedunder reduced pressure. After purifying the residue obtained by silicagel chromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 10/1),0.74 g of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinate was obtained inthe form of a colorless syrup (Yd 75%).

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.82 (2H, d, J=7 Hz), 7.52 (1H, t, J=7.4Hz), 7.45 (2H, t, J=7 Hz), 7.37 (2H, d, J=7.2 Hz), 7.32 (2H, t, J=7.2Hz), 7.26 (2H, m), 5.60 (1H, dd), 4.73 (1H, dt, J=11 and 4.3 Hz), 1.88to 1.67 (m), 1.44 (2H, m), 1.06 and 0.87 (m), 0.80 (m), 0.67 (3H, d, J=7Hz), 0.62 to 0.34 (m).

Example 7

(2R,3S)-N-Benzoyl-O-triethylsilyl-3-phenylisoserine

A solution of 0.644 g (4.655 mmol) of sodium carbonate in 10 mL ofosmosed water was added to a stirred solution at room temperature of 0.5g (0.931 mmol) of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinate in 15 mL ofmethanol. After stirring for 16 h at room temperature and monitoring byT.L.C., the reaction mixture was concentrated under reduced pressure andthe residual aqueous phase was washed with dichloromethane (3×50 mL) andthen acidified to pH 2 by slow addition of a 1 M aqueous HCl solution(10 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL)and the combined organic phases were dried over MgSO₄ and concentratedunder reduced pressure.

0.320 g of (2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserine wasobtained in the form of a white powder (Yd=90%) which exhibited thefollowing characteristics:

400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 8.46 (1H, d, J=9.3 Hz), 7.82 (2H, d,J=7.1 Hz), 7.54 (1H, t, J=7.2 Hz), 7.47 (4H, m), 7.32 (2H, t), 7.36 (1H,t), 5.44 (1H, dd, J=9.2 and 5.5 Hz), 4.64 (1H, d, J=5.6 Hz), 0.77 (9H,m), 0.45 (6H, m).

Example 8

(1S,2R,5S)-(+)-Menthyl(2R,3S)-N-benzoyl-O-(2,2,2-trichloroethoxy)carbonyl-3-phenylisoserinate

480 mg (3.96 mmol) of 4-dimethylaminopyridine were added to a stirredsolution at room temperature under an inert atmosphere of 1.38 g (3.3mmol) of (1S,2R,5S)-(+)-menthyl (2R,3S)-N-benzoyl-3-phenylisoserinate in30 mL of anhydrous dichloromethane. After stirring for 10 min, 540 pL(3.96 mmol) of 2,2,2-trichloroethoxycarbonyl chloride were added over 5min. After stirring for 2 h at room temperature and monitoring byT.L.C., the organic phase was washed with a saturated sodiumhydrogencarbonate solution (2×10 mL) and with a saturated sodiumchloride solution (10 mL), dried over MgSO₄ and concentrated underreduced pressure. After purifying the residue obtained by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 5/1), 1.60g of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-(2,2,2-trichloroethoxy)carbonyl-3-phenylisoserinatewere obtained in the form of a colorless syrup (Yd=82%).

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.82 (2H, d, J=7.4 Hz), 7.53 (1H, t,J=7.4 Hz), 7.44 (4H, m), 7.35 (2H, t, J=7 Hz), 7.29 (1H, t, J=7 Hz),7.09 (1H, d, J=9.3 Hz), 6.0 (1H, dd, J=9.3 and 2.5 Hz), 5.45 (1H, d,J=2.6 Hz), 4.78 and 4.72 (2H, 2d, J=11.9 Hz), 4.77 (1H, m), 1.85 (1H,m), 1.79 (1H, m), 1.65 (2H, m), 1.43 (1H, m), 1.02 (1H, m), 0.96 (1H,m), 0.86 (1H, m), 0.83 (3H, d, J=7 Hz), 0.78 (3H, d, J=6.5 Hz), 0.68(3H, d, J=6.9 Hz).

Example 9

(1S,2R,5S)-(+)-Menthyl (4S,5R)-4-phenyloxazolidin-2-one-5-carboxylate

1 mL (7.28 mmol) of 1 ,8-diazabicylo[5,4,0]undec-7-ene was added to astirred solution at room temperature under an inert atmosphere of 3.96 g(6.62 mmol) of (1 S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-(2,2,2-trichloroethoxy)carbonyl-3-phenylisoserinatein 30 mL of anhydrous dichloromethane. After stirring for 30 min at roomtemperature, the organic phase was washed with 10 mL of a saturatedsodium chloride solution, dried over MgSO₄ and concentrated underreduced pressure. After purifying the residue by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 7/3), 2.18g of the compound cited in the title were obtained in the form of ayellow syrup (Yd=95%).

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.40 (5H, m), 6.09 (1H, s), 4.93 (1H, d,J=5.3 Hz), 4.86 (1H, dt, J=11 and 4.4 Hz), 4.73 (1H, d, J=5.4 Hz), 2.05(1H, m), 1.81 (1H, m), 1.71 (2H, m), 1.54 to 1.41 (3H, m), 1.07 (2H, m),0.94 (3H, d, J=6.5 Hz), 0.88 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz).

Example 10

(1S,2R,5S)-(+)-Menthyl(4S,5R)-N-t-butoxycarbonic-4-phenyloxazolidin-2-one-5-carboxylate

3.8 mL (6.07 mmol) of a 1.6M solution of n-butyllithium in hexane wereadded to a stirred solution at −40° C. under an inert atmosphere of 1.91g (5.52 mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-4-phenyloxazolidin-3-one-5-carboxylate in 20 mL of anhydroustetrahydrofuran. After stirring for 10 min at −40° C., a solution of1.81 g (8.28 mmol) of t-butoxycarbonic anhydride in solution in 5 mL oftetrahydrofuran was added and the reaction mixture was allowed to returnto room temperature over 15 min. After diluting with 50 mL ofdichloromethane and washing with a 2% aqueous HCl solution until a pH=5is obtained, the organic phase was dried (MgSO₄) and concentrated underreduced pressure. After purifying the crude product by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 5/1), 2.12g of the compound cited in the title were obtained in the form of acolorless syrup (Yd=86%).

The compound thus obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.45 to 7.26 (5H, m), 5.19 (1H, d, J=3.7Hz), 4.86 (1H, dt, J=10.9 and 4.5 Hz), 4.66 (1H, d, J=3.7 Hz), 2.05 (1H,m), 1.79 (1H, m), 1.73 (2H, m), 1.62 to 1.24 (3H, m), 1.33 (9H, s), 1.11(2H, m), 0.94 (3H, d, J=6.5 Hz) and (1H, m), 0.89 (3H, d, J=7 Hz), 0.77(3H, d, J=7 Hz).

Example 11

(1S,2R,5S)-(+)-Menthyl(4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylate

0.25 mL (2.17 mmol) of benzoyl chloride was added to a stirred solutionat room temperature under an inert atmosphere of 500 mg (1.45 mmol) of(1S,2R,5S)-(+)-menthyl (4S,5R)-4-phenyloxazolidin-3-one-5-carboxylateand 176 mg (1.16 mmol) of 4-pyrrolidinopyridine in 7 mL of anhydrousdichloromethane. After stirring for 3 h at 50° C., the reaction mixturewas brought back to room temperature and diluted with 20 mL ofdichloromethane. The organic phase was washed with 10 mL of a saturatedsodium chloride solution, dried over MgSO₄ and concentrated underreduced pressure. After purifying the crude product by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 5/1), 300mg of the compound cited in the title were obtained in the form of acolorless syrup (Yd=46%).

The compound thus obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.16 (2H, d, J=7.1 Hz), 7.68 (1H, t),7.53 (4H, m), 7.43 (3H, m), 5.57 (1H, d, J=4.4 Hz), 4.90 (1H, dt, J=10.9and 4.4 Hz), 4.85 (1H, d, J=4.3 Hz), 2.07 (1H, m), 1.80 (1H, m), 1.72(2H, m), 1.47 (3H, m), 1.09 (2H, m), 0.95 (3H, d, J=6.5 Hz), 0.88 (3H,d, J=7 Hz), 0.78 (3H, d, J=7 Hz).

Example 12

(4S,5R)-3-N-Benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acid

A solution of 75 mg (0.543 mmol) of potassium carbonate in 1 mL of waterwas added to a stirred mixture at room temperature of 120 mg (0.266mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylate in 2 mL ofmethanol. After stirring for 30 min, the reaction mixture was dilutedwith 10 mL of water and the aqueous phase was washed with 5 mL ofdichloromethane. After acidifying to pH=4 by means of 1 M HCl, theresidual aqueous phase was extracted with ethyl acetate (3×10 mL). Thecombined organic phases were washed with 5 mL of a saturated sodiumchloride solution, dried over MgSO₄ and concentrated under reducedpressure.

40 mg of (4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acidwere obtained in the form of a white powder (Yd=52%) which exhibited thefollowing characteristics:

400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 12.98 (1H, broad s), 7.95 (2H, d,J=7.1 Hz), 7.63 (1H, t, J=7.4 Hz), 7.50 (2H, t, J=7.5 Hz), 7.42 (2H, m),7.37 (3H, m), 4.90 (1H, d, J=5 Hz), 4.77 (1H, d, J=5 Hz).

Example 13

(4S,5R)-4-Phenyloxazolidin-3-one-5-carboxylic acid

10 mL of a homogeneous solution of 360 mg (8.67 mmol) of NaOH, 3 mL ofmethanol and 0.5 mL of water in pyridine were rapidly added to a stirredsolution at 0° C. under an inert atmosphere of 300 mg (0.867 mmol) of(1S,2R,5S)-(+)-menthyl (4S,5R)-4-phenyloxazolidin-2-one-5-carboxylate, 3mL of methanol and then 0.5 mL of water in 6.5 mL of pyridine. Afterstirring for 20 min at 0° C., the reaction mixture was diluted withwater (30 mL) and washed with dichoromethane (30 mL). After acidifyingto a pH=1, the residual aqueous phase was extracted with ethyl acetate(3×20 mL) and the combined organic phases were dried (MgSO₄) andconcentrated under reduced pressure.

86 mg of (4S,5R)-4-phenyloxazolidin-3-one-5-carboxylic acid were thusobtained in the form of a yellow syrup (Yd=53%) which exhibited thefollowing characteristics:

400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 13.33 (1H, broad s), 8.46 (1H, s),7.38 (5H, m), 4.89 (1H, d, J=5 Hz), 4.75 (1H, d, J=5 Hz).

II. Baccatin III derivatives

Example 14

7-O-Triethylsilyl-10-deacetylbaccatin III

6.2 mL (36.6 mmol) of triethylsilyl chloride were added over 10 min to astirred solution, at room temperature and under an inert atmosphere, of10 g (18.3 mmol) of 10-deacetylbaccatin III and 8.17 g (54.9 mmol) of4-pyrrolidinopyridine in 500 mL of anhydrous dichloromethane. Afterreacting for 3 h at room temperature, 10 g of crushed ice were added andthe mixture was left stirring vigorously for 10 min. The residualorganic phase was washed with water (200 mL), dried over MgSO₄ andconcentrated under reduced pressure.

After treating the crude product obtained with the minimum amount ofethyl acetate, 11.2 g of 7-O-triethylsilyl-10-deacetylbaccatin III wereobtained in the crystalline state (Yd=92.3%).

The product thus obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.4 Hz), 7.60 (1H, t,J=7.5 Hz), 7.47 (2H, t, J=7.6 Hz), 5.60 (1H, d, J=7 Hz), 5.17 (1H, d,J=1.9 Hz), 4.96 (1H, d, J=8 Hz), 4.86 (1H, m), 4.41 (1H, dd, J=10.6 and6.6 Hz), 4.31 and 4.16 (2H, 2d, J=8.4 Hz), 4.26 (1H, d, J=1.9 Hz), 3.95(1H, d, J=6.9 Hz), 2.48 (1H, ddd, J=14.5, 9.7 and 6.7 Hz), 2.29 (3H, s),2.27 (2H, m), 2.08 (3H, s), 1.90 (1H, m), 1.73 (3H, s), 1.62 (1H, s),1.08 (6H, s), 0.94 (9H, t, J=8 Hz), 0.56 (6H, m).

Example 15

7-O-Triethylgermanyl-10-deacetylbaccatin III

80 μL (0.476 mmol) of triethylgermanyl chloride were added over 10 minto a stirred solution, at room temperature and under an inertatmosphere, of 100 mg (0.183 mmol) of 10-deacetylbaccatin III and 41 mg(0.275 mmol) of 4-pyrrolidinopyridine in 4 ml of anhydrousdichloromethane and the mixture was stirred at 50° C. for 13 h. Aftercooling the reaction mixture and diluting with 15 mL of dichloromethane,1 g of crushed ice was added and the mixture was left stirringvigorously for 10 min. The residual organic phase was washed with asaturated sodium hydrogencarbonate solution (5 mL) and a saturatedsodium chloride solution (5 mL), dried over MgSO₄ and concentrated underreduced pressure. After chromatographing the crude product on silica gel(15-40 μm) (eluent: cyclohexane/ethyl acetate, 25/75), 67 mg of7-O-triethylgermanyl-10-deacetylbaccatin III were obtained in the formof a colourless syrup.

The product thus obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.09 (2H, d, J=7.1 Hz), 7.60 (1H, t,J=7.4 Hz), 7.48 (2H, t, J=7.6 Hz), 5.63 (1H, d, J=7.1 Hz), 5.24 (1H, s),4.99 (1H, d, J=8 Hz), 4.78 (1H, t), 4.32 (1H, d, J=8.3), 4.28 (1H, m),4.17 (2H, m), 3.97 (1H, d, J=7 Hz), 2.59 (1H, m), 2.30 (3H, s), 2.24(1H, m), 2.10 (1H, m), 2.03 (3H, s), 1.82 (1H, m), 1.73 (3H, s), 1.11(9H, m), 1.0 (6H, t, J=7.7 Hz).

Example 16

7-O-(2,2,2-Trichloro-t-butoxycarbonyl)-10-deacetylbaccatin III

3.3 g (13.8 mmol) of 2,2,2-trichloro-t-butoxycarbonyl chloride wereadded over 2 h to a stirred solution at 40° C. under an inert atmosphereof 5 g (9.19 mmol) of 10-deacetylbaccatin III and 1.1 mL of anhydrouspyridine in 250 mL of dry dichloromethane. After reacting for anadditional 30 min and returning to room temperature, the organicsolution was washed with a 2% aqueous HCl solution (30 mL), washed withosmosed water (2×100 mL), dried over MgSO₄ and concentrated underreduced pressure (Yd=55%). After chromatographing the crude product onsilica gel (15-40 μm) (eluent: cyclohexane/ethyl acetate, 60/40),7-O-(2,2,2-trichloro-t-butoxycarbonyl)-10-deacetylbaccatin III wasobtained in the form of a white powder.

The product obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7 Hz), 7.62 (1H, t, J=7.4Hz), 7.49 (2H, t, J=7.6 Hz), 5.65 (1H, d, J=6.9 Hz), 5.44 (1H, dd,J=10.8 and 7.3 Hz), 5.39 (1H, d), 4.98 (1H, d, J=7.5 Hz), 4.89 (1H, m),4.35 and 4.20 (2H, 2d, J=8.4 Hz), 4.10 (1H, d, J=7 Hz), 4.01 (1H, d,J=1.8 Hz), 2.64 (1H, m), 2.31 (3H, s), 2.29 (1H, m), 2.11 (3H, d), 2.05(2H, m), 1.89 (3H, s), 1.09 (3H, s), 1.07 (3H, s).

Example 17

a) 7-O-Triethylsilylbaccatin III

0.54 mL (7.5 mmol) of acetyl chloride was added over 10 min to a stirredsolution at room temperature under an inert atmosphere of 1 g (1.5 mmol)of 7-O-triethylsilyl-10-deacetylbaccatin III and 1.25 mL (15 mmol) ofpyridine in 15 mL of dry dichloromethane. After reacting for 2 h at roomtemperature and monitoring by T.L.C., 1 g of crushed ice was added andthe mixture was left stirring vigorously for 10 min. The residualorganic phase was washed with water (2×10 mL), dried over MgSO₄ andconcentrated under reduced pressure. After silica gel chromatography(15-40 μm) (eluent: cyclohexane/ethyl acetate, 60/40), 0.756 g of7-O-triethylsilylbaccatin III was obtained in the form of a white powder(Yd=70%).

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.11 (2H, d, J=7.1 Hz), 7.6 (1H, t,J=7.4 Hz), 7.48 (2H, t, J=7.7 Hz), 6.46 (1H, s), 5.63 (1H, d, J=7 Hz),4.96 (1H, d, J=8.1 Hz), 4.83 (1H, m), 4.49 (1H, dd, J=10.4 and 6.7 Hz),4.31 and 4.15 (2H, 2d, J=8.3 Hz), 3.88 (1H, d, J=7 Hz), 2.53 (1H, m),2.29 (3H, s), 2.27 (2H, m), 2.19 (3H, d, J=0.8 Hz), 2.18 (3H, s), 2.12(1H, d), 1.88 (1H, m), 1.68 (3H, s), 1.65 (1H, s), 1.2 (3H, s), 1.04(3H, s), 0.92 (9H, t), 0.59 (6H, m).

Example 18

7-O-(2,2,2-Trichloro-t-butoxycarbonyl)baccatin III

50 μL (0.695 mmol) of acetyl chloride were added to a stirred solutionat room temperature under an inert atmosphere of 260 mg of7-O-(2,2,2-trichloro-t-butoxycarbonyl-10-deacetylbaccatin III and 127.5mg (1.04 mmol) of 4-dimethylaminopyridine in 2.5 mL of drydichloromethane. After reacting for 1 h at room temperature, the organicphase was washed with a 2% aqueous HCl solution until a pH=6 isobtained, dried over MgSO₄ and concentrated under reduced pressure.After chromatographing the residue obtained on silica gel (15-40 μm)(eluent: cyclohexane/ethyl acetate, 6/4), 0.23 g of7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatin III was obtained in thesolid state (Yd=83%).

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.11 (2H, d, J=7.1 Hz), 7.62 (1H, t,J=7.4 Hz), 7.49 (2H, t, J=7.6 Hz), 6.39 (1H, s), 5.64 (1H, d, J=6.9 Hz),5.61 (1H, dd, J=10.7 and 7.2 Hz), 4.99 (1H, d, J=8.2 Hz), 4.87 (1H, m),4.33 and 4.16 (2H, 2d, J=8.4 Hz), 4.02 (1H, d, J=6.9 Hz), 2.64 (1H, ddd,J=14.4, 9.5 and 7.2 Hz), 2.30 (3H, s) and (2H, m), 2.17 (3H, s), 2.13(3H, d, J=0.8 Hz), 2.04 (1H, m), 1.83 (3H, s), 1.63 (1H, s), 1.14 (3H,s), 1.09 (3H, s).

Example 19

7-O-Phenoxyacetyl-10-deacetylbaccatin III

1.05 mL (7.5 mmol) of phenoxyacetyl chloride were added over 10 min to astirred solution, at room temperature and under an inert atmosphere, of1.03 g (1.88 mmol) of 10-deacetylbaccatin III and 0.6 mL (7.5 mmol) ofanhydrous pyridine in 100 mL of dry dichloromethane. After reacting for30 min at room temperature and monitoring by T.L.C., the organicsolution was washed with a 2% aqueous HCl solution until a pH=2 isobtained, washed with osmosed water (2×50 mL), dried over MgSO₄ andconcentrated under reduced pressure (Yd=70.5%). After chromatographingthe crude product on silica gel (15-40 μm) (eluent: cyclohexane/ethylacetate, 60/40), 7-O-phenoxyacetyl-10-deacetylbaccatin III was obtainedin the form of a white powder.

The product obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.09 (2H, d, J=7.3 Hz), 7.61 (1H, t,J=7.4 Hz), 7.48 (2H, t, J=7.6 Hz), 7.31 (2H, t, J=7.7 Hz), 6.99 (3H, m),6.42 (1H, s), 5.61 (1H, d, J=7 Hz), 4.97 (1H, d, J=7.8 Hz), 4.86 (3H,m), 4.44 (1H, dd, J=10.6 and 6.8 Hz), 4.30 and 4.15 (2H, 2d, J=8.4 Hz),3.86 (1H, d, J=7 Hz), 2.56 (1H, m), 2.27 (3H, s), 2.27 (2H, m), 2.05((3H, s), 1.86 (1H, m), 1.68 (3H, s), 1.01 (3H, s), 0.98 (3H, s).

Example 20

7,10-O-Di(phenoxyacetyl)-10-deacetylbaccatin III

0.5 mL (3.68 mmol) of phenoxyacetyl chloride was added over 10 min to astirred solution, at room temperature and under an inert atmosphere, of500 mg (0.92 mmol) of 10-deacetylbaccatin III and 0.6 mL (7.36 mmol) ofanhydrous pyridine in 50 mL of dry dichloromethane. After reacting for 6h at room temperature and monitoring by T.L.C., the solution was washedwith a 2% aqueous HCl solution until a pH=2 is obtained, washed withosmosed water (2×20 mL), dried over MgSO₄ and concentrated under reducedpressure. After chromatographing the crude product on silica gel (15-40μm) (eluent: cyclohexane/ethyl acetate, 6/4), 0.55 g of7-10-O-bis(phenoxyacetyl)-10-deacetylbaccatin III was obtained in theform of a white powder (Yd=74%).

The product obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.09 (2H, d, J=7.1 Hz), 7.61 (1H, t,J=7.4 Hz), 7.48 (2H, t, J=7.6 Hz), 7.29 (2H, t, J=6.8 Hz), 7.22 (2H, t,J=7.5 Hz), 6.96 (4H, m), 6.84 (2H, d, J=7.9 Hz), 6.42 (1H, s), 5.69 (1H,dd, J=10.5 and 7.1 Hz), 5.60 (1H, d, J=6.9 Hz), 4.96 (1H, d, J=8.2 Hz),4.84 (1H, t, J=7.4 Hz), 4.8 (2H, s), 4.65 and 4.41 (2H, 2d, J=15.8 Hz),4.32 and 4.14 (2H, 2d, J=8.4 Hz), 3.98 (1H, d, J=6.8 Hz), 2.65 (1H, m),2.28 (3H, s), 2.26 (2H, m), 2.09 (3H, s), 1.80 (3H, s) and (1H, m), 0.98(6H, s).

Example 21

7-O-Phenoxyacetylbaccatin III

0.233 mL (3.27 mmol) of acetyl chloride was added over 10 min to astirred solution, at room temperature and under an inert atmosphere, of1.11 g (1.64 mmol) of 7-O-phenoxyacetyl-10-deacetylbaccatin III in 40 mLof anhydrous pyridine. After reacting for 16 h at room temperature andmonitoring by T.L.C., the reaction mixture was diluted with 50 mL ofosmosed water and the aqueous phase was extracted with ethyl acetate(3×30 mL). The combined organic phases were washed with water (2×20 mL),dried over MgSO₄ and concentrated under reduced pressure (Yd=84.5%).After silica gel chromatography (15-40 μm) (eluent: cyclohexane/ethylacetate, 60/40), 7-O-phenoxyacetylbaccatin III was obtained in thecrystalline state.

The product obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.1 Hz), 7.61 (1H, t,J=7.4 Hz), 7.48 (2H, t, J=7.7 Hz), 7.27 (2H, t, J=8 Hz), 6.95 (3H, m),6.26 (1H, s), 5.71 (1H, dd, J=10.4 and 7.2 Hz), 5.62 (1H, d, J=6.9 Hz),4.96 (1H, d, J=8.3 Hz), 4.80 (1H, m), 4.81 and 4.53 (2H, 2d, J=16 Hz),4.32 and 4.14 (2H, 2d, J=8.5 Hz), 4.0 (1H, d, J=6.9 Hz), 2.64 (1H, m),2.29 (2H, m), 2.28 (3H, s), 2.24 (1H, d, J=5 Hz), 2.16 (3H, s), 2.09(3H, d, J=0.7 Hz), 1.81 (1H, m), 1.78 (3H, s), 1.13 (3H, s), 1.08 (3H,s).

Example 22

7-10-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-10-deacetylbaccatinIII

1.28 ml (2.05 mmol) of n-butyllithium as a 1.6M solution in hexane wereadded over 10 min to a stirred solution, at −40° C. and under an inertatmosphere, of 500 mg (0.93 mmol) of 10-deacetylbaccatin III in 20 mL ofanhydrous tetrahydrofuran. After stirring for 5 min, 350 μL (1.12 mmol)of 1,3-dichloro-1,1,3,3-tetraisopropyldisyloxane were added and thereaction mixture was allowed to return to room temperature over 20 min.After stirring for 1 h at room temperature, 225 mg (2.05 mmol) of4-dimethylaminopyridine were added and the reaction mixture was leftstirring for an additional 1 h. After adding 20 mL of a saturatedaqueous sodium chloride solution, the mixture was extracted withdichloromethane (3×30 mL). The combined organic phases were washed witha saturated aqueous sodium chloride solution (20 ml), dried over MgSO₄and concentrated under reduced pressure. After purifying by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 60/40),480 mg of7,10-O-(1,1,3,3-tetraisopropyl-1,3-disyloxanediyl)-10-deacetylbaccatinIII were obtained in the amorphous state (Yd=65%).

The product obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.2 Hz), 7.60 (1H, t,J=7.4 Hz), 7.47 (2H, t, J=7.6 Hz), 5.60 (1H, s), 5.59 (1H, d), 4.97 (1H,d, J=7.9 Hz), 4.87 (1H, m), 4.68 (1H, dd, J=10.4 and 6.9 Hz), 4.30 and4.17 (2H, 2d, J=8.5 Hz), 3.92 (1H, d, J=7.1 Hz), 2.49 (1H, m), 2.28 (3H,s), 2.27 (1H, m), 2.04 (1H, m), 1.91 (1H, m), 1.67 (3H, s), 1.55 (1H,s), 1.32 to 0.85 (34H, m).

Example 23

13-O-[[(4S,5R)-2,4-Diphenyl-4,5-dihydroxazol-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII

2.06 g (10 mmol) of dicyclohexylcarbodiimide were added to a stirredsolution, at room temperature and under an inert atmosphere, of 2.67 g(10 mmol) of (4S,5R)-2,4-diphenyl-4,5-dihydroxazol-5-carboxylic acid in55 mL of anhydrous toluene. After stirring for 5 min, 3.5 g (5 mmol) of7-O-triethylsilylbaccatin III and 0.61 g (5 mmol) of4-dimethylaminopyridine were added and the reaction mixture was broughtto 70° C. for 1 h. After returning to room temperature and removing theinsoluble materials by filtration, the organic phase was concentratedunder reduced pressure. After purifying the crude product by silica gelchromatography (15-25 μm) (eluent: cyclohexane/ethyl acetate, 90/10),4.62 g of13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydroxazol-5-yl]carbonyl-7-O-triethylsilylbaccatinIII were obtained in the crystalline state (Yd=97%).

The compound thus obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.23 (2H, d, J=7.2 Hz), 8.07 (2H, d,J=7.3 Hz), 7.63 (1H, t, J=7.4 Hz), 7.58 (1H, t, J=7.4 Hz), 7.49 (4H, m),7.38 (5H, m), 6.42 ((1H, s), 6.18 (1H, t, J=8.2 Hz), 5.68 (1H, d, J=7.1Hz), 5.60 (1H, d, J=6.5 Hz), 4.95 (2H, d), 4.50 (1H, dd, J=10.5 and 6.7Hz), 4.29 (1H, d, J=8.4 Hz), 4.14 (1H, d, J=8.4 Hz), 3.83 (1H, d, J=7.1Hz), 2.55 (1H, m), 2.37 (1H, dd, J=15.3 and 9.3 Hz), 2.26 (1H, dd,J=15.3 and 8.6 Hz), 2.16 (3H, s),2.07 (3H, s), 1.99 (3H, s), 1.89 (1H,m), 1.72 (1H, s), 1.69 (3H, s), 1.23 (3H, s), 1.19 (3H, s), 0.92 (9H, t,J=8 Hz), 0.57 (6H, m).

Example 24

13-O-[[(4S,5R)-2,4-Diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-phenoxyacetylbaccatin III

380 mg (1.84 mmol) of dicyclohexylcarbodiimide were added to a stirredsolution, at room temperature and under an inert atmosphere, of 490 mg(1.83 mmol) of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic acidin 10 mL of anhydrous toluene. After stirring for 5 min, 660 mg (0.92mmol) of 7-O-phenoxyacetylbaccatin III and 112 mg (0.92 mmol) of4-dimethylaminopyridine were added and the reaction mixture was broughtto 70° C. for 2 h. After returning to room temperature and removing theinsoluble materials by filtration, the organic phase was concentratedunder reduced pressure. After purifying the crude product by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 99/1), 800mg of13-O-[[4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-phenoxyacetylbaccatinIII were obtained in the crystalline state (Yd=90%).

The compound thus obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.18 (2H, d, J=7 Hz), 8.07 (2H, d, J=7.3Hz), 7.63 (1H, t, J=7.4 Hz), 7.59-7.32 (1OH, m), 7.28 (2H, t, J=7.5 Hz),6.94 (3H, m), 6.23 (1H, s) and (1H, m), 5.70 (1H, dd, J=10.4 and 7.1Hz), 5.67 (1H, d, J=7.3 Hz), 5.58 (1H, d, J=7 Hz), 4.93 (2H, d), 4.79and 4.53 (2H, 2d, J=15.9 Hz), 4.30 and 4.13 (2H, 2d, J=8.5 Hz), 3.97(1H, d, J=6.9 Hz), 2.67 (1H, m), 2.38 (1H, dd, J=15.2 and 9.3 Hz), 2.26(1H, dd, J=15.2 and 8.4 Hz), 2.15 (3H, s), 2.02 (3H, s), 1.95 (3H, s)and (1H, m), 1.80 (3H, s), 1.74 (1H, s), 1.25 (3H, s), 1.17 (3H, s).

Example 25

13-O-[[(4S,5R)-2,4-Diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-(2,2,2-trichloro-tbutoxycarbonyl)baccatinIII

27 mg (0.13 mmol) of dicyclohexylcarbodiimide were added to a stirredsolution, at room temperature and under an inert atmosphere, of 35 mg of(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic acid in 3 mL ofanhydrous toluene. After stirring for 5 min, 51 mg (0.065 mmol) of7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatin III and 8 mg (0.065 mmol)of 4-dimethylaminopyridine were added and the mixture was brought to 70°C. for 1 h. After returning to room temperature and removing theinsoluble materials by filtration, the organic phase was concentratedunder reduced pressure and the residue obtained was purified by silicagel chromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 9/1).

0.99 g of the compound cited in the title was thus obtained in the formof a white solid (Yd=67%) which exhibited the following characteristics:

400 MHz¹H NMR (CDCl₃) (δ ppm): 8.18 (2H, d, J=7.2 Hz), 8.07 (2H, d,J=7.3 Hz), 7.65 (1H, t, J=7.4 Hz), 7.59 (1H, t, J=7.3 Hz), 7.52 (4H, m),7.39 (5H, m), 6.35 (1H, s), 6.24 (1H, t, J=8.4 Hz), 5.68 (1H, d, J=7.1Hz), 5.59 (1H, d, J=7 Hz) and (1H, dd), 4.95 (1H, d), 4.94 (1H, d, J=7Hz), 4.31 and 4.15 (2H, 2d, J=8.4 Hz), 3.97 (1H, d, J=6.9 Hz), 2.64 (1H,m), 2.37 (1H, dd, J=15.1 and 6 Hz), 2.27 (1H, dd, J=15.2 and 8.5 Hz),2.16 (3H, s), 2.01 (3H, s), 1.98 (3H, s), 1.83 (3H, s), 1.72 (1H, s),1.25 (3H, s), 1.18 (3H, s).

Example 26

13-O-[[(4S,5R)-2,4-Diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7,10-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-10-deacetylbaccatinIII

7 mg (0.06 mmol) of dicyclohexylcarbodiimide were added to a stirredsolution, at room temperature and under an inert atmosphere, of 4 mg(0.015 mmol) of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic acidin 0.5 mL of anhydrous toluene. After stirring for 5 min, a solution of5 mg (0.0065 mmol) of7,10-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-10-deacetylbaccatinIII and of 1 mg (0.0078 mmol) of 4-dimethylaminopyridine in 1 mL ofanhydrous toluene was added. After stirring for 20 min at roomtemperature, the mixture was brought to 50° C. for an additional 20 min.After returning to room temperature, the organic phase was diluted with5 mL of dichloromethane, washed with 2 mL of a saturated aqueous sodiumchloride solution, dried over MgSO₄ and concentrated under reducedpressure. After purifying the crude product by silica gel chromatography(15-25 μm) (eluent: cyclohexane/ethyl acetate, 7/3), 6 mg of thederivative cited in the title were obtained (Yd=90%) in the amorphousstate.

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.21 (2H, d, J=7.2 Hz), 8.07 (2H, d,J=7.6 Hz), 7.63 (1H, t, J=7.5 Hz), 7.59 (1H, t, J=7.4 Hz), 7.50 (2H, t,J=7.4 Hz), 7.39 (5H, m), 6.26 (1H, t), 5.64 (1H, d, J=7 Hz), 5.59 (1H,d, J=6.9 Hz), 5.54 (1H, s), 4.93 (1H, d, J=6.8 Hz) and (1H, m), 4.68(1H, dd), 4.28 and 4.16 (2H, 2d, J=8 Hz), 3.84 (1H, d, J=7.3 Hz), 2.48(1H, m), 2.35 and 2.25 (2H, 2dd), 2.02 (3H, s), 1.88 (3H, s) and (1H,m), 1.67 (3H, s), 1.63 (1H, s), 1.30 to 0.90 (34H, m).

Example 27

13-O-[[(4S,5R)-3-N-Benzoyl-4-phenyloxazolidin-3-one-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII

28 mg (0.136 mmol) of dicyclohexylcarbodiimide were added to a stirredsolution at room temperature under an inert atmosphere of 40 mg (0.137mmol) of (4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acidin 2 mL of anhydrous toluene. After stirring for 5 min, 30 mg (0.043mmol) of 7-O-triethylsilylbaccatin III and 8 mg (0.066 mmol) of4-dimethylaminopyridine were added and the reaction mixture was broughtto 60° C. for 13 h. After returning to room temperature, the reactionmixture was diluted with 10 mL of dichloromethane and the organic phasewas washed with 5 mL of a saturated sodium chloride solution, dried overMgSO₄ and concentrated under reduced pressure. After purifying by silicagel chromatography (15-14 μm) (eluent: cyclohexane/ethyl acetate, 2/1),13 mg of the derivative cited in the title were obtained in theamorphous state (Yd=31%).

The compound obtained exhibited the following characteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.06 (2H, d, J=7.3 Hz), 7.72 (2H, d, J=7Hz), 7.63 (1H, t, J=7.4 Hz), 7.58 (1H, t, J=7.4 Hz), 7.54 to 7.44 (8H,m), 7.40 (1H, t), 6.44 (1H, s), 6.33 (1H, t), 5.73 (1H, d, J=5.7 Hz),5.67 (1H, d, J=5.7 Hz), 4.96 (1H, d, J=5.8 Hz), 4.88 (1H, d, J=8.3 Hz),4.45 (1H, dd, J=10.4 and 6.6 Hz), 4.27 and 4.12 (2H, 2d, J=8.3 Hz), 3.80(1H, d, J=7 Hz), 2.50 (1H, m), 2.26 (2H, m), 2.19 (3H, s), 2.07 (3H, s),1.98 (3H, s), 1.85 (1H, m), 1.76 (1H, s), 1.67 (3H, s), 1.24 (3H, s),1.23 (3H, s), 0.91 (9H, t, J=7.9 Hz), 0.56 (6H, m).

Example 28

13-O-[[(4S,5R)-4-Phenyloxazolidin-3-one-5-yl]carbonyl]-7,10-O-di(phenoxyacetyl)-10-deacetylbaccatin III

65 mg (0.315 mmol) of dicyclohexylcarbodiimide were added to a stirredsolution, at room temperature and under an inert atmosphere, of 78 mg(0.293 mmol) of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic acidin 3 mL of anhydrous toluene. After stirring for 5 min, a solution of237 mg (0.293 mmol) of 7,10-O-bis(phenoxyacetyl)-10-deacetylbaccatin IIIand 36 mg (0.295 mmol) of 4-dimethylaminopyridine in 3 mL of toluene wasadded and the reaction mixture was brought to 60° C. for 1 h. Afterreturning to room temperature and removing the insoluble materials byfiltration, the organic phase was concentrated under reduced pressureand the crude product obtained was purified by silica gel chromatography(15-40 μm) (eluent: cyclohexane/ethyl acetate, 1/1).

280 mg of the compound cited in the title were thus obtained in theamorphous state (Yd=90%), which compound exhibited the followingcharacteristics:

400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.18 (2H, d, J=7 Hz), 8.06 (2H, d, J=7.1Hz), 7.64 (1H, t, J=7.4 Hz), 7.58 (1H, t, J=7.3 Hz), 7.51 (4H, m), 7.39(5H, m), 7.25 (4H, m), 6.96 (4H, m), 6.85 (2H, d, J=8 Hz), 6.33 (1H, s),6.19 (1H, t, J=9 Hz), 5.68 (1H, dd, J=10.5 and 7.1 Hz), 5.65 (1H, d,J=6.9 Hz), 5.59 (1H, d, J=7 Hz), 4.93 (2H, d, J=7.1 Hz), 4.79 (2H, s),4.63 and 4.40 (2H, 2d, J=15.9 Hz), 4.30 and 4.13 (2H, 2d, J=8.4 Hz),3.94 (1H, d, J=6.9 Hz), 2.68 (1H, m), 2.37 (1H, dd, J=15.3 and 9.3 Hz),2.24 (1H, dd, J=15.3 and 8.7 Hz), 2.02 (3H, s), 1.95 (3H, s), 1.80 (3H,s) and (1H, m), 1.69 (1H, s), 1.12 (3H, s), 1.01 (3H, s).

III. Hemisynthesis

Example 29

Preparation of paclitaxel

a) From13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII

0.6 L (0.6 mol) of a 1 M aqueous HCl solution was added to a stirredsolution, at room temperature and under an inert atmosphere, of 90 g(0.095 mol) of 13-O -[[(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII in a mixture of tetrahydrofuran (1.2 L) and methanol (1.2 L) and thereaction mixture was stirred at room temperature for 4 h 30. Afteradding 3.5 L of a saturated aqueous sodium hydrogencarbonate solution,the solution was kept homogeneous by addition of 6 L of tetrahydrofuranand 6 L of water and the reaction mixture was stirred for an additional1 h 30. After adding 15 L of ethyl acetate and 15 L of osmosed water,the residual aqueous phase was extracted with ethyl acetate (15 L). Theorganic phase was dried over MgSO₄ and concentrated under reducedpressure and the crude product thus obtained was purified by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 1/1).

75 g of taxol were thus isolated in the crystalline state (Yd=95%), thecharacteristics of which were in every respect in accordance with theliterature data.

b) From13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatin III

90 μL (0.09 mmol) of a 1 M aqueous HCl solution were added to a stirredsolution, at room temperature and under an inert atmosphere, of 15 mg(0.0148 mmol) of13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatinIII in a mixture of tetrahydrofuran (0.18 mL) and methanol (0.18 mL) andthe reaction mixture was stirred at room temperature for 8 h. Afteradding 0.6 mL of a saturated aqueous sodium hydrogencarbonate solution,the solution was kept homogeneous by addition of 1 mL of tetrahydrofuranand 1 mL of water and the reaction mixture was stirred for an additional1 h 30. After adding 2.5 mL of ethyl acetate and 2.5 mL of osmosedwater, the residual aqueous phase was extracted with ethyl acetate (2.5mL). The combined organic phases are dried over MgSO₄ and concentratedunder reduced pressure.

14 mg of 7-O-(2,2,2-trichloro-t-butoxycarbonyl)taxol are thus obtainedin the crude state (Yd=93%), which product was used without additionalpurification in the following stage.

30 μL (0.525 mmol) of acetic acid and 22.5 mg (0.344 mmol) of zincpowder were added to a stirred solution at room temperature of 13 mg(0.0128 mmol) of 7-O-(2,2,2-trichloro-t-butoxycarbonyl)taxol in 2 mL ofethyl acetate. After stirring for 2 h 30 at room temperature andmonitoring by T.L.C., and after diluting the reaction mixture with 3 mLof ethyl acetate, the organic phase was washed with osmosed water (1mL), with a saturated aqueous sodium hydrogencarbonate solution (1 mL)and again with water, dried over MgSO₄ and concentrated under reducedpressure.

After chromatographing the crude product on silica gel (15-40 μm)(eluent: cyclohexane/ethyl acetate, 6/4), 9.5 mg of taxol were thusisolated in the crystalline state (Yd=89%).

What is claimed is:
 1. Process for the preparation of taxane side chainprecursors in which a cis-β-arylglycidate derivative of general formulaI

in which Ar represents an aryl radical and R represents a hydrocarbonradical, preferably a linear or branched alkyl or a cycloalkyloptionally substituted by one or more alkyl groups, is converted, so asto regio- and stereospecifically introduce the β-Nalkylamide and the(-hydroxyl or their cyclic precursors in a single stage by a Ritterreaction, which consists either: a of the direct synthesis of a linearchain by reacting a cis-β-arylglycidate derivative of general formula Idefined above with a nitrile of formula R₂—CN in which R₂ represents anaryl radical, in the presence of a protonic acid and of water, in orderto obtain a β-arylisoserine derivative of general formula IIa,

in which Ar, R and R₂ are defined above; or b of the direct synthesis ofa cyclic chain by reacting a cis-β-arylglycidate derivative of generalformula I defined above with a nitrile of formula R′₂—CN in which R′₂represents R₂ defined above or a lower alkyl or lower perhaloalkylradical, such as trichloromethyl, in the presence of a Lewis acid or ofa protonic acid, in anhydrous medium, in order to obtain the oxazolineof general formula IIb

in which Ar, R and R′₂ are defined above.
 2. Process according to claim1, characterized in that R represents an optically pure enantiomer of ahighly sterically hindered chiral hydrocarbon radical.
 3. Processaccording to claim 2, characterized in that R is one of the enantiomersof the menthyl radical, in particular (+)-menthyl.
 4. Process accordingto one of claims 1 to 3, characterized in that the cis-β-phenylglycidatederivative of general formula I is of (2R,3R) configuration and thederivatives of general formulae IIa and IIb obtained are of (2R,3S)configuration.
 5. Process according to claim 4, characterized in that Arand R₂ represent phenyl.
 6. Process according to claim 1, characterizedin that the protonic acid in stage a is chosen from sulfuric acid,perchloric acid, or tetrafluoroboric acid, the Lewis acid in stage b ischosen from the boron trifluoride acetic acid complex, boron trifluorideetherate, antimony pentachloride, tin tetrachloride, or titaniumtetrachloride, and the protonic acid in stage b is tetrafluoroboricacid.
 7. Process according to claim 1, characterized in that theβ-arylisoserine derivative of general formula IIa is converted byprotection of the hydroxyl by an appropriate protective group (GP), inorder to obtain a derivative of general formula II′a

in which Ar, R and R₂ are defined in claim 1 and GP represents aprotective group for the hydroxyl functional group which is appropriatefor the synthesis of taxanes.
 8. Process according to claim 1,characterized in that the β-arylisoserine derivative of general formulaIIa is converted into a novel oxazolidinone cyclic intermediate ofgeneral formula IIIa

in which Ar and R are defined in claim 1 by reacting a β-arylisoserinederivative of general formula IIa according to claim 1 with ahaloalkoxycarbonyl ester, and then cyclized in the presence of a strongorganic base, wherein the strong organic base is optionallydiazabicycloundecene (DBU), and optionally converted subsequently intothe corresponding amide of general formula III′a

in which Ar and R are defined above and R″₂ represents R′₂ definedabove, an alkoxy radical or a linear or branched alkyl radicalcomprising at least one unsaturation.
 9. Process according to claim 1,characterized in that the oxazoline of general formula IIb is hydrolyzedin acidic medium in order to obtain the β-arylisoserine derivative ofgeneral formula IIIb,

in which Ar, R and R′₂ are defined above, and optionally convertedsubsequently into a corresponding amide of general formula III′b

in which Ar, R, R′₂ and R″₂ are defined above.
 10. Process according toclaim 1, characterized in that the cis-β-arylglycidate derivative ofgeneral formula I

in which Ar is as defined in claim 1 and R represents an optically pureenantiomer of a highly sterically hindered chiral hydrocarbon radical,is prepared by reacting the aldehyde of formula Ar—CHO with thehaloacetate of formula X—CH₂—COOR Ar and R being defined above and Xrepresenting a halogen.
 11. Process according to any one of claims 1 to3 and 6 to 10, characterized in that the derivatives of formulae IIa,II′a, IIb, IIIa, III′a, IIIb and III′b, in which R represents a hydrogenatom, are obtained by controlled saponification.
 12. Precursor compoundsof taxane side chains, characterized in that they are selected from thederivatives of following general formula IIb:

in which Ar and R₂ are defined in claim 1, and R represents an opticallypure enantiomer of a highly sterically hindered chiral hydrocarbonradical.
 13. Compounds according to claim 12, characterized in that R isone of the enantiomers of the menthyl radical, optionally (+)-menthyl.14. Compounds according to either one of claim 12 or 13, characterizedin that the cis-β-phenylglycidate derivative of general formula I is of(2R,3R) configuration, and the derivative of formula IIb is of (2R, 3S)configuration.
 15. Precursor compounds of taxane side chains,characterized in that they are selected from the derivatives offollowing general formulae IIIa and III′a:

in which Ar, R and R″₂ are defined as in claim 1 or 8, or R represents ahydrogen atom.
 16. Compounds according to claim 15, characterized inthat they are of (2R,3S) configuration.
 17. Process of claim 2, whereinthe hydrocarbon radical is a cycloalkyl substituted by one or more alkylgroups.
 18. Process of claim 17, wherein the cycloalkyl is a cyclohexyl.19. Process of claim 7, wherein the protective group is selected fromalkoxy ether, aralkoxy ether, aryloxy ether haloalkoxycarbonyl radicals.20. Process of claim 19, wherein the haloalkoxycarbonyl radicals areselected from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl or(β-trimethyl-silylethoxy) methyl groups, tetrahydropyranyl radicals,β-alkoxycarbonyl radicals, β-halogenated ethers, alkylsilyl ethers, andalkoxyacetyl, aryloxyacetyl, haloacetyl or formyl radicals.
 21. Processof claim 10, wherein the halogen is chlorine or bromine.
 22. Processaccording to claim 4, characterized in that the derivatives of formulaeIIa, II′a, IIb, IIIa, III′a, IIIb and III′b, in which R represents ahydrogen atom, are obtained by controlled saponification.
 23. Processaccording to claim 5, characterized in that the derivatives of formulaeIIa, II′a, IIb, IIIa, III′a, IIIb and III′b, in which R represents ahydrogen atom, are obtained by controlled saponification.